POS0352 GENETIC DETERMINANTS OF RESPONSE TO ABATACEPT IN PATIENTS WITH IGG4-RELATED DISEASE
Authors: J. Mahajne, C. Minici, M. Lanzillotta, V. Batani, L. Dagna, E. Della Torre
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> IgG4-related disease (IgG4RD) is a fibro-inflammatory disorder of unknown etiology. Emerging evidence indicates that chronic inflammation in IgG4RD is sustained by persistent mutual activation of antigen-specific B and T lymphocytes. Targeting B-T cell co-stimulation represents, therefore, a rationale therapeutic approach for IgG4RD. <h3>Objectives</h3> Threefold aim of the present work was (i) to assess the efficacy of abatacept (a selective inhibitor of B-T cell co-stimulation based on a replica of CTLA4) for the treatment of IgG4RD; (ii) to study T cell activation in IgG4RD patients; and (iii) to identify functional and genetic predictors of response to abatacept in IgG4RD patients. <h3>Methods</h3> Three patients with active IgG4RD (Pt1-3) were treated with monthly intravenous infusions of abatacept (750mg) for 6 months without concomitant glucocorticoids. All patients underwent 18F-FDG PET scan before treatment and after 6 infusions to assess disease response. To identify functional and genetic predictors of response to abatacept we used multicolour flow-cytometry and Whole Exome Sequencing (WES). Flow-cytometry using CD3, CD19, CD4, CD25, and CTLA4 antibodies was performed to assess CD4+ T cell activation upon exposure to recombinant humanized CD3/CD28 after 120 hours in vitro colture. Results were compared to 10 healthy controls and 10 patients with rheumatoid arthritis (RA). WES was performed to screen for mutations of a panel of 452 genes related to known monogenic immune mediated diseases. <h3>Results</h3> Pt 1 was a 47 years old male with bilateral submandibular gland involvement (Figure - A - <i>arrow</i>; B - <i>arrows</i>) and subcutaneous lesions (B - <i>circle</i>). Pt2 was a 78 years old woman with right orbital pseudotumor (Figure - A – <i>arrow</i>; B - arrow), sinonasal involvement (B - <i>arrowhead</i>), and skin lesions (B - <i>asterisk</i>). Pt3 was a 68 years old woman with left lacrimal and parotid glands involvement (Figure - A - <i>arrows</i>; B - <i>arrows</i>). Abatacept led to a marked decrease of the dimension and 18-F FDG uptake of IgG4RD lesions in Pt1 and Pt2. Pt3 showed increased pathological 18F-FDG uptake of her orbital pseudotumor with minimal morphologic changes at magnetic resonance, consistent with metabolic progression. In vitro, there was no difference in CTLA4 expression at baseline between IgG4RD patients and controls (p&gt;0.05). Yet, upon activation, IgG4RD patients displayed a premature decrease of CTLA4 expression on T cells compared to healthy donors (p&lt;0.01), suggesting a defective T cell inhibition. Similar results were observed in patients with RA. Accordingly, IgG4RD patients showed expansion of activated CD25+ T cells compared to healthy controls (p&lt;0.05). WES of the three IgG4RD patients treated with abatacept found eterozigous germline mutations of LRBA gene (p.Arg2646His (c.7937G&gt;A)) (Pt1), CTLA4 gene (p.Gly109Glu (c.326G&gt;A)) (Pt2), and DOCK8 gene (p.Gln1550Leu (c.4649A&gt;T)) (Pt3). None of these mutations has been previously reported in the medical literature and remains of uncertain significance but all had a CADD score &gt; 20, thus predicting deleterious impact on protein structure. Of note, mutations in LRBA, CTLA4, and DOCK8 genes are all associated with systemic autoimmunity, lymphoproliferation, and immune deficiency. In particular, as opposed to DOCK8 gene, LRBA and CTLA4 genes encode for functionally related proteins as LRBA regulates the reclycing of CTLA4 on T cell membrane upon antigen engagement to inhibit T cell activation. <h3>Conclusion</h3> In the present work we demonstrate that CD4+ T cells from IgG4RD patients show aberrant activation associated with a reduced expression of the inhibitory molecule CTLA4. Yet, not all patients respond to abatacept suggesting that IgG4RD is sustained by additional pathological mechanisms in at least a proportion of patients. Patients responding to abatacept display, indeed, germline mutations of uncertain significance in CTLA4 pathway and may represent ideal candidates for treatment with abatacept. <h3>Reference</h3> [1]Lanzillotta M, et al. Advances in the diagnosis and management of IgG4 related disease. BMJ, 2020:16;369:m1067. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.